Type II diabetes (T2DM) affects more than 5% of the population in Western countries. In the US alone, about 23.6M children and adults have diabetes, and the associated cost was estimated to $174 billion in 2007. The rise in T2DM prevalence is linked to the dramatically increased incidence of obesity, which now affects about a third of the adult US population. Historically, T2DM was only seen in adults, but it is increasin steadily in children where the obesity rate is approaching 17% (2-19 year- old). Insulin resistance and beta-cell dysfunction are key components of the T2DM pathology. Without intervention to reduce insulin resistance and the associated loss of beta-cell mass, T2DM patients can develop a need for insulin therapy similar to type I diabetes patients. Although a range of therapeutics exist for improving insulin resistance and glucose tolerance in T2DM patients, the cost and outcomes for this patient population show there is a dire need for novel therapeutics that target the inflammation that leads to insulin resistance and beta-cell dysfunction in T2DM. This proposal will test if SP16, a new, anti-inflammatory, therapeutic peptide, can be administered orally or by subcutaneous injection, to provide protection against insulin resistance and beta-cell dysfunction in db/db mice. SP16 is a 17 amino acid peptide and our preliminary data show that it improves glucose tolerance and beta-cell function in db/db mice, when administered by intraperitoneal injection. Identifying a practical route of administration is a prerequisite to initiating a formal preclinical development program, working towards submission of an IND application. We anticipate the proposed studies will enable a GLP safety/tox program as well as submission of a follow-on Phase II SBIR application to support this.